Trial Information

Death Receptor-Mediated Apoptosis and Therapy Strategies in Ovarian Cancer

Ovarian cancer remains highly lethal, with an estimated 25,580 new cases and 16,090 death
per year in the US. The most common ovarian cancers arise from the surface epithelium of
the ovary. Approximately 75% of patients with advanced-stage cancer are surgically
incurable. While chemotherapy is a critical component of treatment, the pre-existing and
induced chemoresistance of ovarian cancer cells is a major obstacle in treatment of patients
with advanced disease. Novel strategies to enhance the established therapeutic Defective
apoptosis has been proposed as one of the major mechanisms that lead to malignant
transformation and resistance to therapeutics. Defective apoptosis may result from
increased growth stimulation (oncogenes), decreased growth inhibition (tumor suppressor
genes) or imbalanced apoptosis regulation. Alterations of the Bcl-2 family proteins have
been reported to be associated with chemotherapy resistance in ovarian cancer cells.(1)
Increased anti-apoptosis protein, Bcl-XL, may play a role in preventing apoptosis of ovarian
cancer cells in response to chemotherapy. Conversely, high levels of pro-apoptosis protein,
Bax, are associated with a favorable response to therapy. The role of these and other
apoptotic regulatory proteins in sensitivity/resistance mechanisms to chemotherapy in
patient's ovarian cancer cells are just beginning to be elucidated.

Precision cut tumor slices will be prepared from fresh primary ovarian tumor specimens using
the Krumdieck tissue slicer, followed by ex vivo TRA-8 cytotoxicity assays on the tumor
slices. Tumor-derived tissue slices may be used immediately in short term assays with no
need to isolate or expand tumor cells, thus avoiding potential problems in maintaining cell
viability or selecting variant cells during tumor dispersion or longer periods of in vitro
cell culture. Demonstration of TRA-8-induced apoptosis using primary ovarian tumors in ex
vivo tumor slice cytotoxicity assays can strengthen the rationale for this therapy in this
tumor type and may be used to select patients who would most likely benefit from TRA-8
therapy. The sensitivity of ovarian patient tumors to TRA-8, paclitaxel, and carboplatin
will be evaluated in tumor slice cytotoxicity assays as single agents and in combination.
Slices from different treatment conditions will be paraffin-embedded or frozen for
immunohistochemical evaluation.